Tocenar 50 mg Powder for concentrate for solution for infusion

TOCENAR is indicated for the treatment of adult patients (> 65 years) with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification.

Posology

Dosing regimen

A 5-day dosing regimen in the treatment of AML is recommended. It is recommended that patients be treated for a minimum of 4 cycles: however, a response may take longer than 4 cycles to be obtained. If after 4 cycles, the patientu2019s hematological values (e.g. platelet counts or absolute neutrophil count), have not yet returned to pre-treatment levels or if disease progression occurs (peripheral blast counts are increasing or bone marrow blast counts are worsening), the patient may be considered to be a non-responder and alternative therapeutic options to TOCENAR should be considered. Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required.

Treatment regimen

In a treatment cycle, TOCENAR is administered at a dose of 20 mg/m2 body surface area by intravenous infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose must not exceed 20 mg/m2 and the total dose per treatment cycle must not exceed 100 mg/m2.

The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. If a dose is missed treatment should be resumed as soon as possible. It is possible to use this regimen in an outpatient setting.

Management of myelosuppression and associated complications

Myelosuppression and adverse events related to myelosuppression (thrombocytopenia, anaemia, neutropaenia, and febrile neutropaenia) are common in both treated and untreated patients with AML. Complications of myelosuppression include infections and bleeding. Treatment may be delayed at the discretion of the treating physician, if the patient experiences myelosuppression-associated complications, such as those described below:

• Febrile neutropaenia (temperature u2265 38.5u00b0C and absolute neutrophil count < 1,000/u03bcL)
• Active viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensive supportive care)
• Haemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25,000/u03bcL or any central nervous system haemorrhage)

Treatment with TOCENAR may be resumed once these conditions have improved or have been stabilised with adequate treatment (anti-infective therapy, transfusions, or growth factors).

Method of administration

TOCENAR is administered by intravenous infusion. A central venous catheter is not required. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

TOCENAR is contra-indicated in patients with known hypersensitivity to decitabine or to any of the excipients, listed in section 6.1. TOCENAR is contra-indicated in lactating women (see section 4.7).

Myelosuppression

Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with AML may be exacerbated by treatment with TOCENAR. Therefore, patients are at increased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), with potentially fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated promptly. Myelosuppression caused by TOCENAR is reversible. Complete blood and platelet counts should be performed regularly, as clinically indicated and prior to each treatment cycle. In the presence of myelosuppression or its complications, treatment with TOCENAR may be interrupted and/or supportive measures instituted (see sections 4.2 and 4.8).

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section 4.8).

Special populations

Hepatic impairment

Use in patients with hepatic impairment has not been established. Caution should be exercised in the administration of TOCENAR to patients with hepatic impairment and in patients who develop signs or symptoms of hepatic impairment. Liver function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated (see sections 4.4 and 5.2).

Renal impairment

Use in patients with severe renal impairment has not been studied. Caution should be exercised in the administration of TOCENAR to patients with severe renal impairment (Creatinine Clearance [CrCl] < 30 mL/min). Renal function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated.

Cardiac disease

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore, the safety and efficacy of TOCENAR in these patients has not been established. Cases of cardiomyopathy with cardiac decompensation, in some cases reversible after treatment discontinuation, dose reduction or corrective treatment, have been reported in the post marketing setting. Patients, especially those with cardiac disease history, should be monitored for signs and symptoms of heart failure.

Paediatric patients

Safety and effectiveness in paediatric patients has not been established.

No formal clinical medicine interaction studies with decitabine have been conducted. There is the potential for an interaction with other medicines which are also activated by sequential phosphorylation (via intracellular phosphokinase activities) and/or metabolised by enzymes implicated in the inactivation of decitabine (e.g., cytidine deaminase). Therefore, caution should be exercised if these active substances are combined with decitabine.

Impact of co-administered medicinal products on decitabine

Cytochrome (CYP) 450-mediated metabolic interactions are not anticipated as decitabine metabolism is not mediated by this system but by oxidative deamination.

Impact of decitabine on co-administered medicinal products

Given its low in vitro plasma protein binding (< 1%), decitabine is unlikely to displace co-administered medicinal products from their plasma protein binding. Decitabine has been shown to be a weak inhibitor of P-gp mediated transport in vitro and is therefore, also not expected to affect P-gp mediated transport of co-administered medicinal products (see section 5.2).

Pregnancy

Women of childbearing potential should be advised to use contraceptive measures and avoid becoming pregnant while being treated with TOCENAR. There is no adequate data on the use of TOCENAR in pregnant women. The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, TOCENAR should not be used during pregnancy and in women of childbearing potential not using effective contraception. If TOCENAR is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.

Lactation

It is not known whether decitabine or its metabolites are excreted in breast milk. TOCENAR is contraindicated during breastfeeding; therefore, if treatment with this medicine is required, breastfeeding must be discontinued (see section 4.3).

Fertility

Men should be advised to not father a child during while receiving TOCENAR and for 2 months following completion of treatment. Because of the possibility of infertility as a consequence of TOCENAR therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiation of treatment.

TOCENAR has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects such as anaemia during treatment. Therefore, caution should be recommended when driving a car or operating machines.

Summary of the safety profile

The most important and frequently occurring adverse reaction is myelosuppression and those occurring as a consequence of myelosuppression.

Tabulated list of adverse drug reactions

Description of selected adverse drug reactions

Hematologic adverse drug reactions

The most commonly reported hematologic adverse drug reactions associated with TOCENAR treatment included febrile neutropenia, thrombocytopenia, neutropenia, anaemia and leukopenia. Serious bleeding-related adverse drug reactions, some of which lead to fatal outcome, such as central nervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the context of severe thrombocytopenia, were reported in patients receiving decitabine. Haematological adverse drug reactions should be managed by routine monitoring of complete blood counts and early administration of supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia according to institutional guidelines. For situations where decitabine administration should be delayed, see section 4.2.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving decitabine.

Gastrointestinal disorders

Occurrences of enterocolitis, including neutropaenic colitis, caecitis have been reported during treatment with decitabine. Enterocolitis may lead to septic complications and may be associated with fatal outcome.

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Medicine Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

There is no direct experience of human overdose and no specific antidote. However, early clinical study data in published literature at doses greater than 20 times higher than the current therapeutic dose, reported increased myelosuppression including prolonged neutropenia and thrombocytopenia. Toxicity is likely to manifest as exacerbations of adverse drug reactions, primarily myelosuppression. Treatment for overdose should be supportive.